1. Field of the Invention
This invention lies in the field of fluid therapy in humans, and more particularly in the field of aqueous solutions for parenteral, oral, dialysis, and irrigation therapy which employ at least one of l-lactate anions, pyruvate anions, d- betahydroxybutyrate anions, acetoacetate anions, or mixtures thereof in combination with selected cations.
2. Prior Art
Previously, I have provided improved electrolyte solutions for in vivo and in vitro usage which contain l-lactate and pyruvate anions, and/or d-betahydroxybutyrate and acetoacetate anions in respective defined ratios in combination with defined Na:Cl ratios; see my copending U.S. patent applications Ser. Nos. 748,232 and 747,792, both filed June 24, 1985, and also my copending U.S. patent application Ser. Nos. 747,858 and 748,184, also filed on such date. However, it is now appreciated that the benefits of using l-lactate, pyruvate, d-betahydroxybutyrate, and/or acetoacetate anions need not be restricted by these previously taught relationships of anion pair ratios to Na:Cl ratios.
The prior art indicated in the 37 Background" sections of these earlier patent applications is incorporated by reference into the present application.
Previously, only racemic mixtures of lactate anions containing both d- and l- forms of lactate have been used in aqueous solutions for human parenteral therapy. The other major organic anion used in human parenteral fluids has been acetate. So far as is now known, the natural l-form of lactate anion has heretofore never been used, apart from the unnatural d- form, in human fluid therapy.
Sodium lactate solutions, used in pharmaceutical practices, are not specified in terms of isomeric structure. In the U.S. and British Pharmacopeias, lactate is defined and approval was duly granted for use of the d,l-lactate mixture. Hence, the d,l-lactate is the form used in contemporary pharmaceutical practice. The l-lactate is recognized to be the physiologically predominant form which is metabolized by different pathways and with different effects than is the d-lactate.
The toxicity of d-lactate has been described in humans (see Oh MS et al N Eng J Med 301: 249-251, 1979; Perlmutter, DH et al J Pediatrics 102: 234-238, 1983; Stolberg, L et al N Eno J Med 306: 1344-1348, 1982). Thus, the d- form has now been discovered to cause adverse and toxic effects when administered to mammals. For example, when an aqueous 20 mM/1 d-lactate (or d-lactic acid) is administered parenterally to a rat, swelling of brain tissue is observed because the brain takes in the slowly metabolized d-lactate.sup.- plus an equivalent amount of K.sup.+. With continued administration, coma develops, the cerebral edema worsens and death ensues. In contrast, when l-lactate is similarly administered, the differential concentration of l-lactate between intracellular and extracellular fluid does not cause coma or death. For another example, Veech et al. (Veech, RL and Fowler, RC., "Cerebral Dysfunction and Respiratory Alkalosis During Peritoneal Dialysis with d-Lactate Containing Peritoneal Dialysis Fluids". Am. J. Med., 1987 (in press)) points out that the severe recurrent metabolic alkelemia described by Kenamond et al. ("Severe Recurrent Alkalemia in a Patient Undergoing Continuous Cyclic Peritoneal Dialysis". Am. J. Med., 548-550, 1986) was secondary to an encephalopathy caused by the inclusion of d,l-lactate in routine dialysis fluids. Because of such encephalopathological results, parenteral solutions containing the racemic d,l-lactate anions should not be administered for therapeutic purposes.
All previous commercial formulations of fluids for human therapy use lactate or lactic acid in the racemic d,l form as defined in the United States or British Pharmacopeia (see the United States Pharmacopeia 21st edition, January 1985, p 581, 945-946, 1186; United States Pharmacopeia Convention, Rockville, and British Pharmacopeia 1980, p 250, 666, 667, Her Majesty's Stationary Office, London). Sodium d,l-lactate solutions are currently and conventionally used for three major purposes in current medical practice. First, sodium d,l-lactate solution is used parenterally as an alkalinizing agent to correct acidosis. Secondly, it is used in parenteral fluid therapy to normalize the Na:Cl ratio from the l:l ratio found in normal saline. Thirdly, it is used as the counter ion in peritoneal dialysis solutions. In addition, it could also be used in current hemodialysis to replace the acetate anion, or, in its H.sup.+ form, as an acid to be added to a bicarbonate hemodialysis fluid.
Prior to the teachings contained in my afore referenced USSN 748,232, pyruvate anions d-betahydroxybutyrate anions, and acetoacetate anions in aqueous solution, so far as is now known, were never used in human therapeutic fluids.